N-Benzyladriamycin-14-valerate and drug resistance

Correlation of anthracycline structural modification with intracellular accumulation and distribution in multidrug resistant cells

Leonard Lothstein, Harold M. Wright, Trevor W. Sweatman, Mervyn Israel

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

N-Benzyladriamycin-14-valerate (AD 198) is a highly hydrophobic analogue of Adriamycin (ADR) which can circumvent multidrug resistance (MDR) in various cell lines. Unlike ADR, AD 198 avoids extrusion by P-glycoprotein (P-gp) in AD 198-resistant murine macrophage-like J774.2 cells and localizes in the cytoplasm. To determine the structural modification(s) responsible for these different characteristics, intracellular accumulation and distribution of ADR, AD 198, and the two half-substituted AD 198 congeners, N-benzyladriamycin (AD 288) and adriamycin-14-valerate (AD 48), were analyzed in AD 198-sensitive (J774.2) and -resistant (A300) cells. A300 cells exhibited cross-resistance to and reduced accumulation of ADR, AD 48, and AD 288. ADR and AD 288 rapidly localized in the nuclei of parental and A300 cells, while AD 48 and AD 198 localized in the cytoplasm. AD 48 redistributed into nuclei and cytoplasm of both cell lines, but AD 198 maintained a punctate cytoplasmic distribution in A300 cells. These results suggest that both the N-benzyl and C14-valerate substitutions of AD 198 are required for P-gp circumvention and stable cytoplasmic localization in A300 cells, probably as a result of differing intracellular drug trafficking.

Original languageEnglish (US)
Pages (from-to)341-347
Number of pages7
JournalOncology Research
Volume4
Issue number8-9
StatePublished - Dec 1 1992

Fingerprint

Anthracyclines
Drug Resistance
trichostatin A
Doxorubicin
Cytoplasm
P-Glycoprotein
Drug Trafficking
N-benzyladriamycin-14-valerate
Valerates
Cell Line
Multiple Drug Resistance
Macrophages
adriamycin-14-valerate
N-benzyladriamycin

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

N-Benzyladriamycin-14-valerate and drug resistance : Correlation of anthracycline structural modification with intracellular accumulation and distribution in multidrug resistant cells. / Lothstein, Leonard; Wright, Harold M.; Sweatman, Trevor W.; Israel, Mervyn.

In: Oncology Research, Vol. 4, No. 8-9, 01.12.1992, p. 341-347.

Research output: Contribution to journalArticle

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